Dynamic gating of perceptual flexibility by non-classically responsive cortical neurons.

The ability to flexibly respond to sensory cues in dynamic environments is essential to adaptive auditory-guided behaviors. Cortical spiking responses during behavior are highly diverse, ranging from reliable trial-averaged responses to seemingly random firing patterns. While the reliable responses of 'classically responsive' cells have been extensively studied for decades, the contribution of irregular spiking 'non-classically responsive' cells to behavior has remained underexplored despite their prevalence. Here, we show that flexible auditory behavior results from interactions between local auditory cortical circuits comprised of heterogeneous responses and inputs from secondary motor cortex. Strikingly, non-classically responsive neurons in auditory cortex were preferentially recruited during learning, specifically during rapid learning phases when the greatest gains in behavioral performance occur. Population-level decoding revealed that during rapid learning mixed ensembles comprised of both classically and non-classically responsive cells encode significantly more task information than homogenous ensembles of either type and emerge as a functional unit critical for learning. Optogenetically silencing inputs from secondary motor cortex selectively modulated non-classically responsive cells in the auditory cortex and impaired reversal learning by preventing the remapping of a previously learned stimulus-reward association. Top-down inputs orchestrated highly correlated non-classically responsive ensembles in sensory cortex providing a unique task-relevant manifold for learning. Thus, non-classically responsive cells in sensory cortex are preferentially recruited by top-down inputs to enable neural and behavioral flexibility.

Contributions of cortical neuron firing patterns, synaptic connectivity, and plasticity to task performance.

Neuronal responses during behavior are diverse, ranging from highly reliable 'classical' responses to irregular 'non-classically responsive' firing. While a continuum of response properties is observed across neural systems, little is known about the synaptic origins and contributions of diverse responses to network function, perception, and behavior. To capture the heterogeneous responses measured from auditory cortex of rodents performing a frequency recognition task, we use a novel task-performing spiking recurrent neural network incorporating spike-timing-dependent plasticity. Reliable and irregular units contribute differentially to task performance via output and recurrent connections, respectively. Excitatory plasticity shifts the response distribution while inhibition constrains its diversity. Together both improve task performance with full network engagement. The same local patterns of synaptic inputs predict spiking response properties of network units and auditory cortical neurons from in vivo whole-cell recordings during behavior. Thus, diverse neural responses contribute to network function and emerge from synaptic plasticity rules.

SIRT3 is required for liver regeneration but not for the beneficial effect of nicotinamide riboside.

Liver regeneration is critical to survival after traumatic injuries, exposure to hepatotoxins, or surgical interventions, yet the underlying signaling and metabolic pathways remain unclear. In this study, we show that hepatocyte-specific loss of the mitochondrial deacetylase SIRT3 drastically impairs regeneration and worsens mitochondrial function after partial hepatectomy. Sirtuins, including SIRT3, require NAD as a cosubstrate. We previously showed that the NAD precursor nicotinamide riboside (NR) promotes liver regeneration, but whether this involves sirtuins has not been tested. Here, we show that despite their NAD dependence and critical roles in regeneration, neither SIRT3 nor its nuclear counterpart SIRT1 is required for NR to enhance liver regeneration. NR improves mitochondrial respiration in regenerating WT or mutant livers and rapidly increases oxygen consumption and glucose output in cultured hepatocytes. Our data support a direct enhancement of mitochondrial redox metabolism as the mechanism mediating improved liver regeneration after NAD supplementation and exclude signaling via SIRT1 and SIRT3. Therefore, we provide the first evidence to our knowledge for an essential role for a mitochondrial sirtuin during liver regeneration and insight into the beneficial effects of NR.